Adjuvant medial versus entire supraclavicular lymph node irradiation in high-risk early breast cancer (SUCLANODE): a protocol for a multicenter, randomized, open-label, phase 3 trial

Background Supraclavicular nodal (SCL) irradiation is commonly used for patients with high-risk breast cancer after breast surgery. The Radiation Therapy Oncology Group (RTOG) and European Society for Radiotherapy and Oncology (ESTRO) breast contouring atlases delineate the medial part of the SCL region, while excluding the posterolateral part. However, recent studies have found that a substantial proportion of SCL failures are located in the posterolateral SCL region, outside of the RTOG/ESTRO-defined SCL target volumes. Consequently, many radiation oncologists advocate for enlarging the SCL irradiation target volume to include both the medial and posterolateral SCL regions. Nevertheless, it remains uncertain whether adding the posterolateral SCL irradiation improves survival outcomes for high-risk breast cancer patients. Methods The SUCLANODE trial is an open-label, multicenter, randomized, phase 3 trial comparing the efficacy and adverse events of medial SCL irradiation (M-SCLI group) and medial plus posterolateral SCL irradiation (entire SCL irradiation, E-SCLI group) in high-risk breast cancer patients who underwent breast conserving-surgery or mastectomy. Patients with pathological N2-3b disease following initial surgery, or clinical stage III or pathological N1-3b if receiving neoadjuvant systemic therapy, are eligible and randomly assigned (1:1) to M-SCLI group and E-SCLI group. Stratification is by chemotherapy sequence (neoadjuvant vs. adjuvant), T stage (T3-4 vs. T1-2), N stage (N1-2 vs. N3), and ER status (positive vs. negative). Other radiation volumes are identical in the two arms, including breast/chest wall, undissected axillary lymph node, and internal mammary node. Advanced intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), or tomotherapy techniques are recommended. Both hypofractionated and conventional fractionation schedules are permitted. The primary end point is invasive disease-free survival, and secondary end points included overall survival, SCL recurrence, local-regional recurrence, distance recurrence, safety outcome, and patient-reported outcomes. The target sample size is 1650 participants. Discussion The results of the SUCLANODE trial will provide high-level evidence regarding whether adding posterolateral SCL irradiation to medial SCL target volume provides survival benefit in patients with high-risk breast cancer. Trial registration ClinicalTrials.gov Identifier: NCT05059379. Registered 28 September 2021, https://www.clinicaltrials.gov/ct2/show/NCT05059379.


Background
Numerous randomized clinical trials and meta-analyses have demonstrated that radiotherapy significantly reduces local-regional recurrence and improves diseasefree survival and breast cancer-specific survival in highrisk breast cancer patients after primary breast surgery [1][2][3][4].Additionally, patients with pathologically positive lymph node after neoadjuvant chemotherapy and surgery have been shown to have high risk of recurrence and could benefit from postoperative radiotherapy [5].Based on these evidences, it is recommended that patients with pathologically stage III disease after primary breast surgery, as well as those with pathologically positive lymph nodes following neoadjuvant systemic therapy and breast surgery, should receive postoperative breast/chest wall and regional nodal irradiation (RNI).
The supraclavicular nodal (SCL) region is the most frequent site of regional nodal failure after mastectomy and breast-conserving surgery, thus remained an essential component of RNI [6].In the era of traditional 2-dimensional (2D) radiotherapy, the SCL field was defined based on anatomical boundaries.Typically, the lateral border was located lateral to humeral head with a block to shield the humeral head or medial 2/3 clavicle.Typical radiation dose coverage includes only medial part of SCL region, not extending to the posterolateral SCL fossa [3,4].In the modern radiotherapy era, with the advent of computedtomography (CT)-based radiation treatment planning, atlas consensus was proposed by the Radiation Therapy Oncology Group (RTOG) in 2009 and the European Society for Radiotherapy and Oncology (ESTRO) in 2015 [7,8].The RTOG define the dosal and lateral boundaries of the SCL clinical target volume (CTV) at the anterior aspect of the scalene muscle and lateral edge of sternocleidomastoid muscle (cranial) and the junction of the 1st rib and clavicle (caudal), respectively [7].The ESTRO define the dosal and lateral boundaries of the SCL CTV at pleura and including the anterior scalene muscles and connecting to the medial border of axillary level 3, respectively [8].Therefore, both RTOG and ESTRO consensus still encompass only the medial part of SCL region.
However, several recent studies have focused on mapping the locations of the SCL metastases and have demonstrated a notable SCL metastases occurred in the overlooked posterolateral part of SCL region (14 ~ 82%), thus outside of the RTOG and ESTRO-defined SCL CTVs [9][10][11][12][13].Consequently, a growing number of radiation oncologists advocate for enlarging SCL CTV to include both medial and posterolateral SCL region, creating what is referred to as the "entire SCL region".In the context of ongoing clinical trials, the RADCOMP atlas for RTOG 3509/3510 trial has introduced the posterolateral SCL as an optional volume to consider for irradiation [14].Additionally, a phase 3 randomized clinical trial exploring the impact of internal mammary nodal irradiation on disease-free survival in high-risk breast cancer patients in currently recruited in China, with the SCL CTV encompassing the entire SCL region [15].However, some other clinical trials, such as NRG 9353, Alliance A11022, Danish Breast Cancer Cooperative Group (DBCG) RT Recon Trial, and DBCG HYPO II Trial still define the SCL CTV based on RTOG atlas or ESTRO guidelines.Therefore, controversy exists in practice regarding the optimal definition of the SCL target volume.Recently, TransAtlantic Radiation Oncology Network conducted a review and recommended that SCL CTV should follow the RTOG or the RADCOMP atlas for patients at high and very high regional recurrence risk [16].
We previously conducted a retrospective study comparing cancer outcomes and toxicities between medial SCL irradiation versus entire SCL irradiation in 544 patients with clinical or pathological stage N2-3b breast cancer at our institution from January 2015 to December 2016.With a median follow-up time of 64.2 months, we found no significant differences in the cumulative incidence of SCL recurrence, disease-free survival, or overall survival between the two groups [17].However, high-level evidence is lacking.The current SUCLANODE trial is a randomized trial investigating whether adding posterolateral SCL region to the medial SCL target volume will improve disease-free survival in patients with high-risk early breast cancer.Additionally, acute and late radiation-related toxicities and quality of life will be hypofractionated and conventional fractionation schedules are permitted.The primary end point is invasive diseasefree survival, and secondary end points included overall survival, SCL recurrence, local-regional recurrence, distance recurrence, safety outcome, and patient-reported outcomes.The target sample size is 1650 participants.Discussion The results of the SUCLANODE trial will provide high-level evidence regarding whether adding posterolateral SCL irradiation to medial SCL target volume provides survival benefit in patients with high-risk breast cancer.

Study design
The SUCLANODE trial is an open label, multicenter, randomized, phase 3 trial comparing the efficacy and adverse events of medial SCL irradiation (M-SCLI group) versus entire SCL irradiation (E-SCLI group) in patients with high-risk early breast cancer after breast conserving-surgery or mastectomy.High-risk is defined as follows: pN2-3b disease if surgery was the initial treatment, or cIII or ypN1-3a/b if neoadjuvant systemic therapy was the initial therapy.The target sample size is 1650 participants.We hypothesize that E-SCLI, which includes the posterolateral SCL fossa in the SCL CTV, provide superior disease-free survival compared to M-SCLI group.The Flow chart of this trial is summarized in Fig. 1.

Primary endpoint
The primary endpoint is disease-free survival (DFS), defined as the time from the date of randomization to the date of the first occurrence of any following events: ipsilateral invasive local recurrence (including ipsilateral breast tumor recurrence, ipsilateral chest wall recurrence), ipsilateral invasive regional recurrence (including axillary, supraclavicular, or internal mammary nodes), distant recurrence, contralateral invasive breast cancer, or death from any cause.

Secondary endpoints
1. Overall survival: Defined as the time from randomization to death from any cause.2. SCL lymph node recurrence: Defined as the time from randomization to the date of the first ipsilateral supraclavicular lymph node recurrence.3. Local-regional recurrence: Defined as the time from randomization to the date of the first ipsilateral breast, chest wall, axillary, supraclavicular, or internal mammary nodal recurrence.

Exploratory outcome
To explore whether radiotherapy resistance mechanisms can be identified through analysis of tumor and blood sample derivatives.Future exploratory research into factors that may influence efficacy and safety may be performed on the collected and stored tumor and blood samples.Efficacy outcomes considered for this analysis will include local-regional recurrence and DFS, as appropriate.

Inclusion criteria
1. Female subjects aged 18 ~ 75 yeas on the day of signing informed consent.

Randomization
Eligible patients will be centrally randomized in a 1:1 ratio to the M-SCLI group and the E-SCLI group.Randomization will be stratified according to the following factors: neoadjuvant systemic therapy vs. adjuvant systemic therapy; T3-4 vs. T1-2; N3 vs. non-N3; ER positive vs. ER negative.

Treatment arms
Trial participants will be allocated to two treatment groups:

Radiation therapy Localization, simulation, and immobilization
Patients should be optimally positioned supine using breast boards, wing boards and/or other immobilization devices per treating physician' discretion.Radio-opaque markers will be placed on the skin at scar, inframammary fold, and superior border of the breast tissue.A treatment planning CT scan will be performed with an image thickness of ≤ 0.5 cm. for patients who underwent mastectomy, an additional PTV_CW_EVA is generated by limiting the ventral border of PTV_CW at skin surface for DVH evaluation.

Clinical target volumes (CTVs)
Organs at risk (OARs) Normal structures include heart, left anterior descending, ipsilateral lung, contralateral lung, contralateral breast, humeral head, thyroid, esophagus, and brachial plexus.Of these structures, left anterior descending are optional.

Dose specifications
Both hypofractionated and conventional fractionated radiation therapy are permitted: the conventional fractionated regimen is 50 Gy in 25 fractions of 2 Gy; the hypofractionated schedule is 42.5 Gy in 16 fractions of 2.67 Gy.Tumor bed or scar boost is at the discretion of the treating physician, boost doses will be 10 ~ 16 Gy in 5 ~ 8 fractions of 2 Gy, for total cumulative doses of 60 ~ 66 Gy.

Technique factors and treatment planning
3D-conformal radiation therapy (3D-CRT) techniques are not recommended due to significant incidental irradiation of the SCL region.Advanced intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), or tomotherapy techniques are recommended instead.Methods to minimize the cardiac Suggested PTV compliance criteria are as follows: at least 95% of each PTV receives ≥ 95% of the prescribed dose (it is acceptable if ≥ 95% of each PTV receives ≥ 90% of the prescribed dose, except for PTV_IMN, it is acceptable if ≥ 90% of the PTV_IMN receives ≥ 90% of the prescribed dose); the maximum point dose (volume that is 0.03 cm 3 ) is recommended to be ≤ 115% of the prescription dose (≤ 120% acceptable), and should be evaluated without the contribution of the boost fields; ≤ 35% of the PTV_B_EVA, PTV_CW_EVA, or PTV_IMN receives 100% of the boost prescribed dose when a boost is included in the composite plan (≤ 40% acceptable); ≤ 5% of the PTV_TB_EVA receives ≥ 110% of the boost prescribed dose (≤ 10% acceptable).
The OARs dose constraints are shown in Table 2.

Treatment verification
Before the first time of radiotherapy, portal films or 3D-CRT images (e.g., conebeam CT, MV CT, kV CT) must be obtained and approved by a physician.During radiotherapy, portal films or 3D-CRT images must be obtained every 5 fractions.

Follow-up
During radiotherapy, patients will attend the clinic every 2 weeks and at the end of treatment.Physical examination, hematology tests, and acute radiation toxicity (including acute radiation dermatitis, pneumonitis, esophagitis, neck and should pain, and myocardial ischemia/infarction) will be performed.After completing radiotherapy, efficacy assessments for recurrence, new cancers and overall survival will be conducted every 3 months for the first 2 years, every 6 months for the years 3 ~ 5, and then annually until 10 years from randomization.Efficacy follow-up includes symptoms assessment, physical examination, hematology tests, blood chemistry/tumor-markers tests, Ultrasounds, mammogram annually, and chest CT scans annually.Breast magnetic resonance imaging (MRI) is permitted in doubtful cases.Additional imaging such as positron emission tomography /computed tomography (PET/CT), bone emission computed tomography (ECT), brain MRI, or biopsy will be performed as indicated for suspected recurrence or metastasis.Acute radiation adverse events will be assessed until 3 months after completing radiotherapy.Late radiation adverse events will be assessed starting at 3 months after completing radiotherapy and then annually.The follow-up workflow is shown in Table 3.

Sample size and statistical analysis
The primary endpoint is DFS.According to data from a Chinese prospective study, the 5-year DFS for high-risk patients after breast-conserving surgery or mastectomy is 73% [19] (control group).We assume a clinically meaningful difference in 5-year DFS of 5% between groups.The hypothesis of the current study is that the 5-year DFS will be superior in the E-SCLI group (experiment group) compared to the M-SCLI group (control group), with a 5-year DFS increase from 73% in the M-SCLI group to 78% in the E-SCLI group.Sample size calculation for comparing DFS was performed with a two-sided α = 0.05 and 80% power.Hazard ratio is 0.79.This yields to a total sample size of 1500 patients.Accounting for a 10% dropout rate, the total sample size is increased to 1650 patients (825 per group).Based on these assumptions, it is estimated that 510 events will be required for the final analysis.Statistical analysis will be performed based on the intent-to-treat principle, with all patients analyzed as randomized, regardless of eligibility or protocol compliance.

Ethics
The trial was approved by the fudan university shanghai cancer center ethics committee (2108241-22).The study is registered in ClinicalTrails.gov(NCT04320979).

Trial status
Patient accrual was started on September 1, 2021 and is currently ongoing.

Discussion
In the current report, we present the protocol of the SUCLANODE trial, which aims to investigate whether adding the posterolateral SCL irradiation to medial SCL irradiation improves DFS in high-risk breast cancer patients after breast surgery.SCL irradiation is widely used for patients with high-risk breast cancer treated with mastectomy and breast-conserving surgery.However, the optimal SCL target volume has been controversial in recent years, high-level data directly comparing entire versus medial SCL irradiation in high-risk breast cancer patients treated with surgery is lacking.
For high-risk patients with less than N3c disease receiving modern adjuvant systemic therapy and radiotherapy, the risk of posterolateral SCL recurrence may be quite low.In our prior retrospective study comparing medial versus entire SCL irradiation in 544 patients with clinical or pathologic N2-N3b disease after breast surgery, only 2 patients (0.4%) had posterolateral SCL recurrence, including 1 who received entire SCL irradiation and had in-field recurrence.Entire SCL irradiation did not significantly improve SCL control and DFS compared to medial SCL irradiation [17].Another study by Bazan et al. reported a similarly low 0.4% rate of posterolateral SCL recurrence (1/268) in high-risk breast cancer patients treated with IMRT (168 patients) or 3D-CRT technique (72 patients) [20].In that study, all CTVs were delineated according to the RTOG breast contouring atlas consensus, thus only the medial SCL region was irradiated.None of the patients in the IMRT group had posterolateral SCL recurrence, indicating a very low risk of recurrence in that region even unintentionally excluded from IMRT treatment volumes in those high-risk patients.The one patient with posterolateral SCL recurrence was treated with 3D-CRT technique, which delivered a mean dose of 4647 cGy to the posterolateral SCL region.This evidence suggests posterolateral SCL recurrence after adjuvant RNI may not be attributable to inadequate target volume coverage.
The biophysical effects of radiotherapy are not tumorspecific and can also cause toxicity due to exposure of surrounding normal tissues.The toxicity is of particular concern in breast cancer as more patients become longterm survivors due to advances in systemic and local therapies.Expanding the SCL target volume will inevitably increase neck and shoulder radiation dose, potentially heightening acute and late normal tissue toxicity and reducing quality of life.Bazan et al. found 3D-CRT technique delivered significantly higher incidental dose to the shoulder and back versus IMRT technique, with a tend toward reduced q-DASH scores indicating less shoulder morbidity in patients treated with IMRT technique (p = 0.078) [20].Our prior study also observed Abbreviations: RT = radiation therapy; CT = computer tomography; MRI = magnetic resonance imaging; PROs = patient reported outcomes; QoL = quality of life a significantly higher rate of pain in the E-SCLI group compared to M-SCLI (26.6% vs. 15.1%,p = 0.005) [17].In this trial, we will evaluate shoulder function via q-DASH questionnaire, patients-reported shoulder/back symptoms, and quality of life.Additionally, a previous study showed 3D-CRT technique delivered significantly higher incidental radiation dose to the posterolateral SCL region than IMRT technique (46.7 Gy vs. 30.2Gy P < 0.0001) when treating medial SCL region based on RTOG consensus [20].We will utilize advanced IMRT, VMAT, or tomotherapy techniques instead of 3D-CRT technique to minimize incidental irradiation to the posterolateral SCL region in the M-SCLI arm.

Conclusion
In conclusion, the SUCLANODE trial is a superiority, multicenter, randomized controlled trial that compares the efficacy and safety of medial SCL irradiation and entire SCL irradiation in patients with high-risk breast cancer after breast surgery.We anticipate that the results of the current trial will provide high-level evidence to optimize the SCL irradiation target volume.

Fig. 2
Fig. 2 Atlas of medial supraclavicular CTV (CTV_M_SCL) and entire supraclavicular CTV (CTV_E_SCL).A: CTV_M_SCL (red).B: CTV_E_SCL (red).Abbreviations: CTV = clinical target volume 4. Distance recurrence: Defined as the time from randomization to the date of the first distant breast cancer recurrence. 5. Safety outcomes: The frequency and severity of acute and late radiation-related adverse events are assessed and graded based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, or RTOG/the European Organization for Research and Treatment of Cancer (EORTC) late radiation morbidity scale and LENT-SOMA criteria if CTCAE grading not available.6. Patient-reported outcomes: Assessment of treatment-related symptoms, health-related quality of life via the EORTC Quality of Life Questionnaire (EORTC-QLQ-C30; version 3) and breast cancer module (QLQ-BR23), and upper limb function via the Quick Disabilities of the Arm, Shoulder and Hand (q-DASH) questionnaire.
Radiation therapy must begin no later than 12 weeks after the last breast cancer surgery or the last dose of adjuvant chemotherapy.8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 9. Acquirement of informed consent.
6. Will receive endocrine therapy for at least 5 years for estrogen receptor (ER) and/or progesterone receptor (PR) positive patients; will receive anti-HER2 (human epidermal growth factor receptor 2) therapy for 1 year for HER2 positive patients.7.

Table 1
Suggested CTV delineation for breast, chest wall, and lymph node regions [7,8,18] include ipsilateral chest wall/breast, supraclavicular lymph nodes, undissected axilla (including interpectoral lymph nodes), and internal mammary nodes, with a tumor bed boost to the lumpectomy cavity for patients who underwent breast-conserving surgery.For patients who received mastectomy, a boost to the scar is delivered only when indicated.If positive internal mammary nodes are identified on initial CT and/or MRI, a nodal boost may be delivered at the discretion of the treating physician.In general, CTV delineation will follow the RTOG and ESTRO guidelines[7,8,18].However, for some controversial areas, modifications have been made at Fudan University Shanghai Cancer Center to establish institutional guidelines for CTV delineation.The suggested CTV delineation for breast, chest wall, and lymph node regions is provided in Table1.ing PTV_TB, PTV_B, PTV_CW, PTV_SCL, PTV_IMN, and PTV_unALN.For patients who underwent breastconserving surgery, additional PTV_B_EVA and PTV_ TB_EVA are generated by limiting the ventral border of PTV_B and PTV_TB at 5 mm beneath the skin surface for dose volume histogram (DVH) evaluation.Similarly, Abbreviations: CTV=clinical target volume; CT=computer tomography

Table 3
Follow-up workflow Additional imaging such as positron emission tomography /computed tomography (PET/CT), bone emission computed tomography (ECT), brain (MRI), or biopsy will be performed as indicated for suspected recurrence or metastasis *